WO2013130890A1 - Composés hétérobicycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase - Google Patents

Composés hétérobicycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase Download PDF

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WO2013130890A1
WO2013130890A1 PCT/US2013/028436 US2013028436W WO2013130890A1 WO 2013130890 A1 WO2013130890 A1 WO 2013130890A1 US 2013028436 W US2013028436 W US 2013028436W WO 2013130890 A1 WO2013130890 A1 WO 2013130890A1
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cyclobutyl
pyridin
pyrrolo
imidazo
dimethyl
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PCT/US2013/028436
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English (en)
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Jennifer R. Allen
Albert Amegadzie
Kristin L. Andrews
James Brown
Jian J. Chen
Ning Chen
Essa Hu Harrington
Qingyian Liu
Thomas T. Nguyen
Alexander J. Pickrell
Wenyuan Qian
Shannon Rumfelt
Robert M. Rzasa
Chester Chenguang Yuan
Wenge Zhong
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Amgen Inc.
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Priority to MX2014010377A priority Critical patent/MX2014010377A/es
Priority to AU2013225838A priority patent/AU2013225838A1/en
Priority to JP2014560058A priority patent/JP2015508826A/ja
Priority to CA2865980A priority patent/CA2865980A1/fr
Priority to EP13709033.8A priority patent/EP2820014A1/fr
Publication of WO2013130890A1 publication Critical patent/WO2013130890A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • heterobicyclic compounds that are PDE10 inhibitors, pharmaceutical compositions containing such compounds, and processes for preparing such compounds.
  • Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.
  • cAMP and cGMP cyclic nucleotide monophosphates
  • PKA cAMP-dependent protein kinase
  • Downstream mediators of cGMP signaling also include kinases and ion channels. In addition to actions mediated by kinases, cAMP and cGMP bind directly to some cellular proteins and directly regulate their activities.
  • Cyclic nucleotide monophosphates are produced from the actions of adenylyl cyclase and guanylyl cyclase, which convert ATP to cAMP and GTP to cGMP. Extracellular signals, often through the actions of G protein-coupled receptors, regulate the activities of the cyclases. Alternatively, the amount of cAMP and cGMP may be altered by regulating the activities of the enzymes that degrade cyclic nucleotide monophosphates. Cell homeostasis is maintained by the rapid degradation of cyclic nucleotide mono-phosphates after stimulus- induced increases.
  • PDEs 3 ',5'-cyclic nucleotide-specific phosphodiesterases
  • PDE1-PDE1 1 Eleven PDE gene families (PDE1-PDE1 1) have been identified based on their distinct amino acid sequences, catalytic and regulatory characteristics, and sensitivity to small molecule inhibitors. These families are coded for by 21 genes; and further multiple splice variants are transcribed from many of these genes. Expression patterns of each of the gene families are distinct. PDEs differ with respect to their affinity for cAMP and cGMP. Activities of different PDEs are regulated by different signals. For example, PDE1 is stimulated by Ca 2+ /calmodulin.
  • PDE2 activity is stimulated by cGMP.
  • PDE3 is inhibited by cGMP.
  • PDE4 is cAMP specific and is specifically inhibited by rolipram.
  • PDE5 is cGMP-specific.
  • PDE6 is expressed in retina.
  • PDE10 sequences were identified by using bioinformatics and sequence information from other PDE gene families (Fujishige et al, J. Biol. Chem. 274: 18438-18445, 1999; Loughney et al, Gene 234: 109-1 17, 1999; Soderling et al, Proc. Natl. Acad. Sci. USA 96:7071-7076, 1999).
  • the PDE10 gene family is distinguished based on its amino acid sequence, functional properties and tissue distribution.
  • the human PDE10 gene is large, over 200 kb, with up to 24 exons coding for each of the splice variants.
  • the amino acid sequence is characterized by two GAF domains (which bind cGMP), a catalytic region, and alternatively spliced N and C termini. Numerous splice variants are possible because at least three alternative exons encode N termini and two exons encode C-termini.
  • PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP. The K m values for cAMP and cGMP are 0.05 and 3.0 micromolar, respectively. In addition to human variants, several variants with high homology have been isolated from both rat and mouse tissues and sequence banks.
  • the tissue distribution of PDE 10 indicates that PDE 10 inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE 10 enzyme, for example, in neurons that comprise the basal ganglia and therefore would be useful in treating a variety of neuropsychiatric conditions involving the basal ganglia such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive compulsive disorder, and the like.
  • the present invention comprises a new class of heterobicyclic compounds useful in the treatment of diseases, such as PDElO-mediated diseases and other maladies, such as schizophrenia, bipolar disorder, or obsessive-compulsive disorder. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of PDElO-mediated diseases and other maladies, such as schizophrenia, bipolar disorder, or obsessive-compulsive disorder, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
  • diseases such as PDElO-mediated diseases and other maladies, such as schizophrenia, bipolar disorder, or obsessive-compulsive disorder.
  • this invention is directed to a compound of Formula (I):
  • each p and q is independently 0, 1, 2, 3, 4, 5, or 6; wherein the sum of p and q is 1, 2, 3,
  • n 0, 1, 2, 3, or 4;
  • A is a 9- to 10-membered heterocyclic ring having the formula:
  • J is independently N or CR 3c ; wherein each E, X, Y, and Z is independently N or
  • R 1 is a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 5- or 6-membered monocyclic ring, or a saturated, partially-saturated or unsaturated 9- or 10-membered bicyclic ring, wherein each said ring contains 0,1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R1 is independently substituted by 0, 1, 2 or 3 R9 groups;
  • R 2 is independently H, OH, Ci- 4 alk, a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R 2 Ci- 4 alk or monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups;
  • each R 3a and R 3c is independently H, F, OH, Ci_ 4 alk, or Ci_ 4 haloalk;
  • R 3b is independently F, CI, Br, CN, OH, OCi_ 4 alk, Ci_ 4 alk, Ci_ 4 haloalk, or oxo;
  • R 4 is halo, R 4a , -SR 4a , -OR 4a , -NHR 4a , or -N(Ci- 4 alk)R 4a , wherein -R 4a is H,
  • Ci_ 4 alk a saturated, partially-saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms;
  • each R 4 Ci_ 4 alk or monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups;
  • each R 5 is independently R 5a , -OR 5b , -NHR 5a , or -N(Ci_ 4 alk)R 5a , wherein R 5a is
  • Ci_ 4 alk a saturated, partially-saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms
  • R 5b is Ci_ 4 alk, a saturated, partially-saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms;
  • each R 5 Ci_ 4 alk or monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups;
  • each R 6 and R 7 is independently H, halo, OH, Ci_ 4 alk, OCi_ 4 alk, a saturated, partially-saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R 6 and R 7
  • Ci- 4 alk or monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups;
  • R 6 and R 7 may optionally form a saturated or partially-saturated 3-, 4-, 5- or
  • each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein said monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups;
  • R 8 is R 8a , -0-R 8a , -NHR 8a , or -N(d_ 4 alk)R 8a , wherein R 8a is H, Ci_ 4 alk, a saturated, partially-saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R 8 Ci_ 4 alk or monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups;
  • R 9 is independently F, CI, Br, Ci_ 6 alk, Ci_ 4 haloalk, -OR a , OR c , -OCi_ 4 haloalk,
  • R a is independently H or R b ;
  • R c is independently a carbon-linked or nitrogen-linked saturated, partially- saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a saturated, partially-saturated or unsaturated 6-, 7-, 8-, 9-, 10-, 1 1-, or 12-membered bicyclic ring, said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are O or S; R c is
  • R 3c , m, p and q are as defined above.
  • the compound of Formula (I) has the structure shown below:
  • E, X, Y, and Z is independently N or CR 4 ; wherein 1 or
  • J is CR 3 ; and each R 5 is independently H, Ci-4alk, -O-
  • Ci-4alk or a saturated 3-, 4-, 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein said monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • J is N; and each R 5 is independently H, Ci-4alk, -O-
  • C2- 4 alk or a saturated 3-, 4-, 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein said monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • each R 6 and R 7 is independently R 6 and R 7 is independently H, halo, OH, 0-Ci_ 4 alk, Ci_ 4 alk or a saturated 3-, 4-, 5- or 6-membered monocyclic ring; or unsaturated 5- or 6-membered monocyclic ring; wherein each said ring contains 0, 1, or 2 N atoms and 0, 1, or 2 O or S atoms; wherein said R 7 Ci_ 4 alk or monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • each R 6 and R 7 is independently H, OH, F, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl or methoxy.
  • each R 6 and R 7 is independently H, F, or methyl.
  • R 6 and R 7 form a saturated 3-, 4-, 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein said monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • R 7 is H, Ci- 4 alk or a saturated 3-, 4-, 5- or 6-membered monocyclic ring; or unsaturated 5- or 6-membered monocyclic ring; wherein each said ring contains 0, 1, or 2 N atoms and 0, 1, or 2 O or S atoms; wherein said R 7 Ci- 4 alk or monocyclic ring is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • R 8 is independently H, Ci- 4 alk, -OCi- 4 alk,
  • R 8 is NH 2 or CF 3 .
  • the group -W-T-D ⁇ is -CR 6 R 7 -(S0 2 )-N ⁇ .
  • the group -W-T-D ⁇ is -NR 7 -(S0 2 )-N ⁇ .
  • each R 5 and R 7 is cyclopropyl.
  • the sum of p and q is 1.
  • the sum of p and q is 2.
  • the sum of p and q is 3.
  • the sum of p and q is 4.
  • J is N.
  • J is N and G is R 1 .
  • J is CR 3c
  • the ring containing p and q is piperidinyl.
  • the ring containing p and q is azetidinyl.
  • the group and the sum of p and q is 2 or 4.
  • R 1 is a saturated, partially-saturated or unsaturated 5- or
  • each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R 1 is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • R 1 is unsaturated 6- membered monocyclic ring
  • each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R 1 is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • R 1 is a saturated, partially-saturated or unsaturated 9- or
  • each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R 1 is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • R 1 is unsaturated 9- or 10-membered bicyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R 1 is independently substituted by 0, 1, 2 or 3 R 9 groups.
  • R 1 is phenyl, oxazolyl, pyridothiazolyl, pyridooxazolyl, pyridimidazolyl, pyrazimidazolyl, pyrimidimidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, pyrazolyl, triazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinaxolinyl, naphthyridinyl, pyridimidazolyl, pyridopyrazolyl, or thiazolo[5,4-b]pyridinyl.
  • R 1 is thiazolyl, oxazolyl, benzoxazolyl, quinazolinyl, quinolinyl, pyridinyl, benzimidazolyl, benzthiazolyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, or 1,8-naphthyridinyl.
  • R 2 is H, OH, or methyl.
  • R 2 is H.
  • R 2 is pyridinyl
  • each R 3a and R 3b is H. OH, F, or CN.
  • m is 0.
  • R 3a and R 3c is H and m is 0.
  • R 9 is F, Br, CI, methyl, ethyl, -OCH 2 F, -OCHF 2 , -OCF 3 ,
  • G is R 1 .
  • J is -CH or -CCH 3 and G is -NR X R 2 .
  • J is -CH or -CCH 3 and G is -NR X R 2 ; wherein R 1 is unsaturated 9- or 10-membered bicyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each R 1 is independently substituted by 0, 1, 2 or 3 R 9 groups, and R 2 is H.
  • J is -CH or -CCH 3 and G is -NR X R 2 ; wherein R 1 is benzimidazolyl, benzoxazolyl, benzthiazolyl, and R 2 is H.
  • J is -CH or -CCH 3 and G is -NR X R 2 ; wherein R 1 is quinolinyl, isoquinolinyl, quinazolinyl, quinaxolinyl, naphthyridinyl, pyridimidazolyl, pyridopyrazolyl, or thiazolo[5,4-b]pyridinyl and R 2 is H.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt, tautomer, or a stereoisomer thereof; as in any one of the preceding embodiments, and a pharmaceutically acceptable excipient.
  • this invention is directed to a method of treating conditions that may be treated with PDE10 inhibitors comprising the step of administering a compound, or a pharmaceutically-acceptable salt thereof, as in any one of the preceding embodiments.
  • said condition is selected from the group consisting of psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention deficit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease, dementia and mania with caudate and pallidal diseases, and compulsions with pallidal disease.
  • said condition is selected from the group consisting of schizophrenia, Huntington's disease, bipolar disorder, and obsessive- compulsive disorder.
  • said condition is schizophrenia.
  • said condition is Huntington's disease.
  • said compound of Formula (I), a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as in any one of the preceding embodiments, is administered in combination with another anti-psychotic agent.
  • the anti-pychotic agent is selected from the group consisting of Clozaril, Zyprexa, Risperidone, and Seroquel.
  • this invention is directed to a method of making a compound of Formula (I), a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as in any one of the preceding embodiments.
  • this invention is directed to said compound of Formula (I), a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as in any one of the preceding embodiments, selected from the group consisting of:
  • the compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of mixtures of enantiomers, partially racemic mixtures, separate enantiomers, mixtures of diastereomers, or separate diastereomers.
  • the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of the present invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H, carbon, such as n C, 13 C and 14 C, chlorine, such as 38 C1, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as N and N, oxygen, such as O, O and O, phosphorus, such as P, and sulphur, such as 35 S.
  • Certain isotopically-labelled compounds of the present invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon- 14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de- acetone, d 6 -DMSO.
  • Ci- 6 alkyl means an alkyl group comprising a minimum of a and a maximum of ⁇ carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein a and ⁇ represent integers.
  • the alkyl groups described in this section may also contain one or two double or triple bonds.
  • a designation of Coalk indicates a direct bond. Examples of Ci- 6 alkyl include, but are not limited to the following:
  • Halo or "halogen” means a halogen atoms selected from F, CI, Br and I.
  • C a -phaloalk means an alk group, as described above, wherein any number— at least one— of the hydrogen atoms attached to the alk chain are replaced by F, CI, Br or I.
  • carbon- linked means a substituent is linked to another group through a carbon atom.
  • Examples of “carbon-linked” substituents include, but are not limited to the following:
  • nitrogen-linked means a substituent is linked to another group through a nitrogen atom.
  • examples of "nitrogen-linked” substituents include, but are not limited to the followin :
  • the group NR a R a and the like include substituents where the two R a groups to ether form a ring, optionally includin a , O or S atom, and include groups such as: [00361 ]
  • the group N(C a _palk)C a _palk, wherein a and ⁇ are as defined above, include substituents where the two C a _palk groups together form a ring, optionally including a N, O or S atom, and include groups such as:
  • “Pharmaceutically-acceptable salt” means a salt prepared by conventional means, and are well known by those skilled in the art.
  • the “pharmacologically acceptable salts” include basic salts of inorganic and organic acids, including but not limited to
  • hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
  • suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like.
  • pharmaceutically acceptable salts see infra and Berge et al, J. Pharm. Sci. 66: 1 (1977).
  • “Saturated, partially-saturated or unsaturated” includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens.
  • leaving group generally refers to groups readily displaceable by a
  • nucleophile such as an amine, a thiol or an alcohol nucleophile.
  • leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to,
  • N-hydroxysuccinimide N-hydroxybenzotriazole, halides, triflates, tosylates and the like.
  • Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like.
  • Preferred protecting groups are indicated herein where appropriate.
  • amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
  • aralkyl examples include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts.
  • aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
  • cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like.
  • Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl, phthaloyl and the like.
  • a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
  • Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, l,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
  • the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.
  • Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
  • aralkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
  • Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2- bis(dimethylsilyl)benzene, l,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a ⁇ , ⁇ , ⁇ -trisilyl derivative.
  • silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
  • Suitable silylating agents are, for example, trimethylsilyl chloride, tert- butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF.
  • Protecting groups can be removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride.
  • a suitable solvent system such as dioxane or methylene chloride.
  • the resulting amino salt can readily be neutralized to yield the free amine.
  • Carboxy protecting group such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
  • Prodrugs of the compounds of Formula (I) are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • Sulfonyl means a -SO 2 radical where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, each as defined herein, e.g., methylsulfonyl, phenylsulfonyl, benzylsulfonyl, pyridinylsulfonyl, and the like.
  • Treating" or "treatment” of a condition or disease includes: preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound of Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C and most preferably at about room (or ambient) temperature, e.g., about 20 °C.
  • Compound 1 which can be cis or trans isomers, or mixtures thereof, can be reacted with R ⁇ -LG, wherein LG is a leaving group such as halogen, sulfonate or perfluorosulfonate, in a suitable solvent such as DMSO or dioxane at ambient or more preferably at elevated temperature in the presence of a mild base, such as CS 2 CO 3 , K 2 CO 3 , or amine base, such as triethylamine, to provide compound 2.
  • a mild base such as CS 2 CO 3 , K 2 CO 3
  • amine base such as triethylamine
  • Compound 2 is then reacted with an amine deprotecting agent, such as concentrated, strong acid (such as HCl or CF 3 COOH), or hydrogenolysis condition, to afford compound 3, which can subsequently react with suitably substituted heterocyclic compounds 4 via a direct SNAr reaction or a metal- catalyzed C-N coupling reaction, wherein LG' is a leaving group such as halogen, sulfonate or perfluorosulfonate, to provide compound 5.
  • an amine deprotecting agent such as concentrated, strong acid (such as HCl or CF 3 COOH), or hydrogenolysis condition
  • LG' is a leaving group such as halogen, sulfonate or perfluorosulfonate
  • Compound 5 is then reacted with a nitro group reducing agent, such as Fe/NH 4 C1, FL/Pd-C, or the like, to provide compound 6.
  • compound 6 can then be reacted under a coupling reaction condition with an appropriate acid, such as HATU coupling, or acid chloride containing R 5 , wherein R 5 is an alkyl or aryl group, to give amide 7, which can be reacted under condensation or dehydration conditions to provide a compound of Formula (IA), wherein R 5 is an alkyl or aryl group.
  • an appropriate acid such as HATU coupling, or acid chloride containing R 5 , wherein R 5 is an alkyl or aryl group
  • Compound 6 can be treated under condensation condition, such as with an orthocarbonate reagent under acidic condition, to provide a compound of Formula (IA), wherein R 5 is an alkoxy group.
  • compound 1 as described above in Scheme 1 a, can be reacted in under coupling reaction condition, with a suitably substituted heterocyclic compound 4, as described above in Scheme la, in the presence of a solvent, such as DMSO, DMF, or dioxane, at ambient or more preferably at elevated temperature, in the presence of a mild base, such as CS 2 CO 3 or K 2 CO 3 , or amine base, such as triethylamine, to provide compound 8.
  • a solvent such as DMSO, DMF, or dioxane
  • a mild base such as CS 2 CO 3 or K 2 CO 3
  • amine base such as triethylamine
  • Compound 9 can then be reacted under a coupling reaction condition with an appropriate acid, such as HATU coupling, or acid chloride containing R 5 , wherein R 5 is an alkyl or aryl group, to give amide 10, which can be reacted under an appropriate acid, such as HATU coupling, or acid chloride containing R 5 , wherein R 5 is an alkyl or aryl group, to give amide 10, which can be reacted under
  • condensation or dehydration conditions to provide a compound of Formula (IA), wherein R 5 is an alkyl or aryl group.
  • Compound 9 can be treated under condensation condition, such as with an orthocarbonate reagent under acidic condition, to provide compound 11 , which can then be reacted with a amine deprotecting group, an amine deprotecting agent, such as concentrated, strong acid (such as HCl or CF 3 COOH), or hydrogenolysis condition, followed by reaction with a reagent of formula R ⁇ -LG, wherein LG is a leaving group, such as halogen, sulfonate or perfluorosulfonate, to provide a compound of Formula (IA), wherein R 5 is an alkoxy group.
  • compound of Formula (IB) can be prepared from compound 14.
  • Compound 14, wherein LG is a leaving group such as halogen, sulfonate or perfluorosulfonate, and R is a Ci- 6 alkyl or benzyl, can be prepared under several reaction conditions, for example from compound 12 or compound 13.
  • Compound 12 is generally commercially available or can be synthesized via selective synthetic methods as described in this invention as heterocyclic halide, preferably chloride, which can be converted to compound 14 by metal-catalyzed ⁇ -arylation reactions with suitably substituted acetates, such as tert-butyl isobutyrate.
  • Compound 13 is generally commercially available heteroaryl substituted acetates, which can be converted to compound 14 by metal-catalyzed -arylation, or under basic alkylation condition reactions, such as with the use of LiHMDS, with a suitably substituted alkylating or arylating agent containing R 6 and R 7 , such as methyliodide or phenylbromide.
  • compound 14 can be reacted under hydrolysis reaction condition, to provide compound 15, which can then be reacted with compound 1 or compound 3, as defined in above Scheme la, to provide compound 16, wherein Q is an amine protecting group, such as Boc or Cbz, or R 1 .
  • compound 16 When Q is an amine protecting group, compound 16 can then be reacted with a strong base, such as LiHMDS, at ambient or elevated temperatures to provide compound 17, wherein Q is a protecting group. Such protecting group can then be removed with a deprotecting agent, and the deprotected compound 17 may be reacted with R X -LG under general coupling conditions, such as SNAr or C-N coupling, to provide a compound of Formula (IB).
  • Q When Q is R 1 , compound 16 can then be reacted with a strong base, such as LiHMDS, at ambient or elevated temperatures to provide compound 17, which is a compound of Formula (IB), as defined above. Alternatively, compound 16 may be reacted under Buchwald amidation conditions or similar conditions to provide compound 17.
  • compound of Formula (IB) can be prepared from compound 19.
  • Compound 19 wherein LG is a leaving group such as halogen, sulfonate or perfluorosulfonate can be prepared under several reaction conditions, for example from compound 12, as described above in General Scheme 3, or compound 18.
  • Compound 12 can be converted to compound 19 by metal-catalyzed cc-arylation reactions with a suitably substituted acetonitrile, such as 2,3-dichloropyrazine.
  • Compound 18 is generally commercially available heteroaryl substituted acetonitrile, or can be prepared using the methods described in this invention, which can be converted to compound 19 by metal- catalyzed cc-alkylation or arylation, or under basic condition reactions, such as NaH or NaHMDS, with a suitably substituted alkylating or arylating agent containing R 6 and R 7 , such as l-bromo-2-chloroethane or phenylbromide.
  • compound 19 can be reacted with compound 1, as defined in above Scheme la, in the presence of a strong base, such as LiHMDS or NaO l Bu, at ambient or elevated temperatures, or under metal-catalyzed amination conditions, after acidic work up or acid treatment of reaction mixture at ambient or elevated temperature, to provide compound 17, wherein Q is a protecting group such as Carbobenzyloxy (Cbz) or H wherein tert-Butyloxycarbonyl (Boc) is the protecting group for 1.
  • a strong base such as LiHMDS or NaO l Bu
  • Such protecting group can then be removed with a deprotecting agent, and the deprotected compound 17 may then be reacted with R X -LG under general coupling conditions, such as SNAr or C-N coupling, to provide a compound of Formula (IB).
  • compound 19 can then be reacted with compound 3 in the presence of a strong base, such as LiHMDS, or under Buchwald conditions, at ambient or elevated temperatures to provide compound of Formula (IB), as defined above.
  • a strong base such as LiHMDS, or under Buchwald conditions
  • reaction with R 2 -LG wherein LG is a leaving group such as halogen, sulfonate or perfluorosulfonate, can be performed earlier in the methods, for example to compound 1 or compound 3, or any suitable compounds which may be ultimately converted to compounds of Formulae (IA) and (IB), wherein R 2 is other than H.
  • LG is a leaving group such as halogen, sulfonate or perfluorosulfonate
  • a cyclizating agent such as CDI, triphosgene
  • compound of Formula (IC) can be prepared by reacting compound 9, which can be prepared according to the above General Scheme 2, with a cyclizating agent, such as CDI, triphosgene, optionally in the presence of a base, such as triethylamine, or orthoformate in the presence of an acid such as propionic acid, at ambient or elevated temperature to provide compound 20, wherein PG is an amine protecting group, such as Boc or Cbz, which can be deprotected with a deprotecting agent, such as hydrochloric acid, trifluoroacetic acid, or under hydrogenolysis condition, followed by reaction with a reagent of formula R ⁇ -LG, wherein LG is a leaving group, such as halogen, sulfonate or perfluorosulfonate, to provide a compound of Formula (IC), wherein R 2 is H.
  • a cyclizating agent such as CDI, triphosgene
  • a base such as triethylamine
  • orthoformate in the presence of an acid such as
  • Such compounds of Formula (IC), wherein R 2 is H, can be further reacted with R 2 -LG, wherein LG is a leaving group such as halogen, sulfonate or perfluorosulfonate, in the presence of a strong base and/or at more elevated temperatures, to form a compound of Formula (IC) wherein in the final products, R 2 is other than H.
  • LG is a leaving group such as halogen, sulfonate or perfluorosulfonate
  • R2 H Formula (IC) wherein R 2 is not H
  • Boc Boc or Cbz leaving groups, e.g.,
  • each LG and LG' is independently a leaving group such as halogen, sulfonate or perfluorosulfonate, in the presence of a strong base, such as LiHMDS, at ambient or elevated temperatures, or under metal-catalyzed amination conditions, to provide compound 22, wherein Q is a protecting group or R 1 as defined herein, and LG' is a leaving group, such as halogen, sulfonate or perfluorosulfonate.
  • Compound 22 can then be reacted with an amine reagent, such as R 7 - H 2 , under metal catalyzed amination condition to provide compound 23.
  • Compound 23 can then be reacted with a cyclizating agent, such as CDI, triphosgene, optionally in the presence of a base, such as triethylamine, or orthoformate in the presence of an acid such as propionic acid, at ambient or elevated temperature to provide compound 24, wherein Q is an amine protecting group, or provide a compound of Formula (IC) wherein Q is R 1 .
  • a cyclizating agent such as CDI, triphosgene
  • a base such as triethylamine
  • orthoformate in the presence of an acid such as propionic acid
  • Q is an amine protecting group
  • protecting group of compound 24 can then be reacted with a deprotecting agent, such as hydrochloric acid, trifluoroacetic acid, or under hydrogenolysis condition, followed by reaction with a reagent of formula R ⁇ -LG, wherein LG is a leaving group, such as halogen, sulfonate or perfluorosulfonate, to provide a compound of Formula (IC), wherein both R 2 is H.
  • a deprotecting agent such as hydrochloric acid, trifluoroacetic acid, or under hydrogenolysis condition
  • Such compound of Formula (IC) can be further reacted with R 2 -LG, wherein LG is a leaving group such as halogen, sulfonate or perfluorosulfonate, in the presence of a strong base and/or at more elevated temperatures, to form a compound of Formula (IC), wherein in the final products, R 2 is other than H.
  • LG is a leaving group such as halogen, sulfonate or perfluorosulfonate
  • Such compound of Formula (IC) can be further reacted with R ⁇ LG, optionally followed by R 2 -LG, wherein LG is a leaving group such as halogen, sulfonate or perfluorosulfonate, in the presence of a strong base and/or at more elevated temperatures, to form a compound of Formula (IC), wherein in the final products, R 1 , R 2 , or both R 1 and R 2 are independently other than H.
  • LG is a leaving group such as halogen, sulfonate or perfluorosulfonate
  • R 2 is H
  • compound of Formula (ID) can be prepared from compound 28, which can be prepared according to methods described herein.
  • Compound 28 can be reacted with hydrazine to provide compound 29, which can be reacted with an amine protecting group to provide compound 30.
  • Compound 30 can then be selectively deprotected under standard hydrogenation conditions to provide compound 31.
  • Reaction of compound 31 with various R ⁇ LG reagents under general SNAr or C-N coupling conditions provides compound 32, which can be further deprotected by reaction with a deprotecting agent, such as hydrochloric acid, trifluoroacetic acid, to provide compound 33, which then can be treated with a commercially available heteroaryl nitrile compound 34 or a readily available heteroaryl ketone compound 35 to provide a compound of Formula (ID) wherein R 2 is H.
  • a deprotecting agent such as hydrochloric acid, trifluoroacetic acid
  • Such compounds of formula (ID), wherein R 2 is H, can be further reacted with R 2 -LG, wherein LG is a leaving group such as halogen, sulfonate or perfluorosulfonate, in the presence of a strong base and/or at more elevated temperatures, to form a compound of Formula (ID) wherein in the final products, R 2 is other than H.
  • LG is a leaving group such as halogen, sulfonate or perfluorosulfonate
  • SNAr reactions are reactions in which a nucleophile such as an amine or alcohol reacts with an electrophile, such as aryl or heteroaryl halides or sulfonates or perflurosulfonates, usually in the presence of a base, such as triethylamine or K 2 C0 3, at ambient or elevated temperature in suitable solvents, such as THF, DMF, or DMSO.
  • C-N coupling conditions are reactions that form a new C-N bond by directly joining together a nitrogen-containing group, such as an amino group or amido group as a formal nucleophile and a formal electrophile such as aryl or heteroaryl halides or sulfonates or perflurosulfonates.
  • C-N coupling reactions can also take place in an intramolecular fashion to form a new ring structure.
  • Such C-N coupling reactions are catalyzed by metal-based catalysts such as a palladium- or copper-based catalyst and usually are conducted in the presence of a base such as LiHMDS or triethylamine at ambient or elevated temperatures in suitable organic solvents such as dioxane, THF, or DMF. (Do you want to move this to Scheme 1?)
  • GENERAL SCHEME 10 PREPARATION OF COMPOUNDS OF FORMULA (IE).
  • compound of Formula (IE) can be prepared according to methods of General Schemes 3 to 7, wherein compound 1 or 3 is replaced with compounds 36, 37, or 38.
  • Compound of Formula (IF), wherein J is N can be prepared according to methods of General Schemes 1 and 2, wherein compound 1 or 3 is replaced with compounds 36, 37, or 38.
  • General Scheme 1 1 describes preparation of a compound of Formula (IF), wherein J is CH and G is -(C ⁇ R 1 or -(CHOH)R 1 .
  • compound 39 wherein P is N(OCH 3 )(CH 3 ) or OR, wherein R is simple alkyl such as methyl or ethyl, which is commercially available or can be prepared according to procedures described herein, may be converted to compound 40, wherein P is N(OCH 3 )(CH 3 ) or OR, wherein R is simple alkyl such as methyl or ethyl, which is commercially available or can be prepared according to procedures described herein, according to methods analogous to General Schemes 1 and 2, wherein reactions or irawsformations involving compound 1 or 3 can be conducted with compound 39.
  • a R ⁇ derived organometallic reagent such as M-R 1
  • GENERAL SCHEME 11 M-R 1 M metal, e.g., Li +
  • kits for treating a disorder or disease by inhibiting PDE10 enzyme comprise the step of administering a therapeutically effective amount of a compounds of the present invention, or an individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, to a patient in need thereof to treat the disorder or disease.
  • this invention provides a use of a compound as described herein in the manufacture of a medicament for treating a disorder or disease treatable by inhibition of PDE10.
  • the compounds of the present invention inhibit PDE10 enzyme activity, and hence raise the levels of cAMP or cGMP within cells that express PDE10. Accordingly, inhibition of PDE10 enzyme activity would be useful in the treatment of diseases caused by deficient amounts of cAMP or cGMP in cells. PDE10 inhibitors would also be of benefit in cases wherein raising the amount of cAMP or cGMP above normal levels results in a therapeutic effect. Inhibitors of PDE10 may be used to treat disorders of the peripheral and central nervous system, cardiovascular diseases, cancer, gastro-enterological diseases, endocrinological diseases and urological diseases.
  • Indications that may be treated with PDE10 inhibitors include, but are not limited to, those diseases thought to be mediated in part by the basal ganglia, prefrontal cortex, and hippocampus. These indications include psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention deficit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease, dementia and mania with caudate and pallidal diseases, and compulsions with pallidal disease.
  • ADHD attention deficit/hyperactivity disorder
  • Psychoses are characterized by delusions and hallucinations.
  • the compounds of the present invention are suitable for use in treating patients suffering from all forms of psychoses, including, but not limited to, schizophrenia, late-onset schizophrenia, schizoaffective disorders, prodromal schizophrenia, and bipolar disorders. Treatment can be for the positive symptoms of schizophrenia as well as for the cognitive deficits and negative symptoms.
  • Other indications for PDE10 inhibitors include psychoses resulting from drug abuse (including amphetamines and PCP), encephalitis, alcoholism, epilepsy, Lupus, sarcoidosis, brain tumors, multiple sclerosis, dementia with Lewy bodies, or hypoglycemia.
  • Other psychiatric disorders like posttraumatic stress disorder (PTSD), and schizoid personality may also be treated with PDE10 inhibitors.
  • the compounds of the present invention have utility in treating a variety of neurological and psychiatric disorders associated with inhibition of PDE10, including one or more of the following conditions or diseases: schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance- induced or drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive
  • Creutzfeldt- Jacob disease perinatal hypoxia, other general medical conditions or substance abuse
  • delirium amnestic disorders or age related cognitive decline
  • anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic attack, panic disorder, post- traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition
  • substance-related disorders and addictive behaviors including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics
  • bipolar disorders mood disorders including depressive disorders; depression including unipolar depression, seasonal depression and postpartum depression, premenstrual syndrome (PMS) and premenstrual dysphoric, disorder (PDD), mood disorders due to a general medical
  • medication-induced parkinsonism such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic- induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor
  • Gilles de la Tourette's syndrome epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias [including tremor (such as rest tremor, postural tremor and; intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), and dystonia (including generalised dystonia such as iodiopathic dys
  • Obsessive-compulsive disorder has been linked to deficits in the frontal- striatal neuronal pathways (Saxena et al, Br. J. Psychiatry Suppl, 35:26-37, 1998). Neurons in these pathways project to striatal neurons that express PDE10. PDE10 inhibitors cause cAMP to be elevated in these neurons; elevations in cAMP result in an increase in CREB
  • OCD may result, in some cases, from streptococcal infections that cause autoimmune reactions in the basal ganglia (Giedd et al, Am J Psychiatry. 157:281-283, 2000). Because PDE10 inhibitors may serve a neuroprotective role, administration of PDE10 inhibitors may prevent the damage to the basal ganglia after repeated streptococcal infections and thereby prevent the development of OCD.
  • cAMP or cGMP In the brain, the level of cAMP or cGMP within neurons is believed to be related to the quality of memory, especially long term memory. Without wishing to be bound to any particular mechanism, it is proposed that, since PDE10 degrades cAMP or cGMP, the level of this enzyme affects memory in animals, for example, in humans.
  • a compound that inhibits cAMP phosphodiesterase (PDE) can thereby increase intracellular levels of cAMP, which in turn activate a protein kinase that phosphorylates a transcription factor (cAMP response binding protein).
  • the phosphorylated transcription factor then binds to a DNA promoter sequence to activate genes that are important in long term memory. The more active such genes are, the better is long-term memory. Thus, by inhibiting a phosphodiesterase, long term memory can be enhanced.
  • Dementias are diseases that include memory loss and additional intellectual impairment separate from memory.
  • the compounds of the present invention are suitable for use in treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementias (e.g.
  • Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease vascular (e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld- Jacob Disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g., vitamin B 12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g., depression and schizophrenia), and hydrocephalus.
  • vascular e.g., infarcts, hemorrhage, cardiac disorders
  • mixed vascular and Alzheimer's e.g., bacterial meningitis, Creutzfeld- Jacob Disease, multiple sclerosis
  • traumatic e.g., subdural hematoma or traumatic brain injury
  • infectious e
  • the condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information.
  • the present invention includes methods for dealing with memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline.
  • MCI mild cognitive impairment
  • the present invention includes methods of treatment for memory impairment as a result of disease.
  • Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.
  • the compounds of the present invention are suitable for use in the treatment of memory impairment due to, for example, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA),
  • the compounds of the present invention are also suitable for use in the treatment of a class of disorders known as polyglutamine-repeat diseases. These diseases share a common pathogenic mutation.
  • the expansion of a CAG repeat, which encodes the amino acid glutamine, within the genome leads to production of a mutant protein having an expanded polyglutamine region.
  • Huntington's disease has been linked to a mutation of the protein huntingtin. In individuals who do not have Huntington's disease, huntingtin has a polyglutamine region containing about 8 to 31 glutamine residues. For individuals who have Huntington's disease, huntingtin has a polyglutamine region with over 37 glutamine residues.
  • Aside from Huntington's disease (HD) other known polyglutamine-repeat diseases and the associated proteins include dentatorubral-pallidoluysian atrophy, DRPLA (atrophin-1);
  • spinocerebellar ataxia type- 1 (ataxin-1); spinocerebellar ataxia type-2 (ataxin-2);
  • spinocerebellar ataxia type-3 also called Machado-Joseph disease or MJD
  • MJD Machado-Joseph disease
  • spinocerebellar ataxia type-6 alpha la- voltage dependent calcium channel
  • spinocerebellar ataxia type-7 ataxin-7
  • spinal and bulbar muscular atrophy SBMA, also know as Kennedy disease.
  • the basal ganglia are important for regulating the function of motor neurons; disorders of the basal ganglia result in movement disorders. Most prominent among the movement disorders related to basal ganglia function is Parkinson's disease (Obeso et al, Neurology. 62(1 Suppl 1):S 17-30, 2004). Other movement disorders related to dysfunction of the basal ganglia include tardive dyskinesia, progressive supranuclear palsy and cerebral palsy, corticobasal degeneration, multiple system atrophy, Wilson disease, dystonia, tics, and chorea. The compounds of the invention are also suitable for use to treat movement disorders related to dysfunction of basal ganglia neurons.
  • PDE10 inhibitors are useful in raising cAMP or cGMP levels and prevent neurons from undergoing apoptosis.
  • PDE10 inhibitors may be anti-inflammatory by raising cAMP in glial cells.
  • Autoimmune diseases or infectious diseases that affect the basal ganglia may result in disorders of the basal ganglia including ADHD, OCD, tics, Tourette's disease, Sydenham chorea.
  • any insult to the brain can potentially damage the basal ganglia including strokes, metabolic abnormalities, liver disease, multiple sclerosis, infections, tumors, drug overdoses or side effects, and head trauma.
  • the compounds of the invention can be used to stop disease progression or restore damaged circuits in the brain by a combination of effects including increased synaptic plasticity, neurogenesis, anti-inflammatory, nerve cell regeneration and decreased apoptosis.
  • cAMP and cGMP The growth of some cancer cells is inhibited by cAMP and cGMP.
  • cells may become cancerous by expressing PDE10 and reducing the amount of cAMP or cGMP within cells.
  • inhibition of PDE10 activity inhibits cell growth by raising cAMP.
  • PDE10 may be expressed in the transformed, cancerous cell but not in the parent cell line.
  • PDE10 inhibitors reduce the growth rate of the cells in culture.
  • breast cancer cells are inhibited by administration of PDE10 inhibitors.
  • Many other types of cancer cells may also be sensitive to growth arrest by inhibition of PDE10. Therefore, compounds disclosed in this invention can be used to stop the growth of cancer cells that express PDE10.
  • the compounds of the invention are also suitable for use in the treatment of diabetes and related disorders such as obesity, by focusing on regulation of the cAMP signaling system.
  • PDE-10 especially PDE-10A
  • intracellular levels of cAMP are increased, thereby increasing the release of insulin-containing secretory granules and, therefore, increasing insulin secretion.
  • WO 2005/012485 which is hereby incorporated by reference in its entirety.
  • the compounds of Formula (I) can also be used to treat diseases disclosed in US Patent application publication No. 2006/019975, the disclosure of which is incorporated herein by reference in its entirety.
  • PDE10 inhibitory activities of the compounds of the present invention can be tested, for example, using the in vitro and in vivo assays described in the Biological Examples below.
  • the compounds of Formula (I) can be administered in a
  • a compound of this invention i.e., the active ingredient, depends upon numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.1-1000 mg per day; preferably 0.5 to 250 mg/day, more preferably 3.5 mg to 70 mg per day.
  • compounds of Formula (I) can be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • the preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulations depend on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5, 145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of, in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I).
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the level of the compound of Formula (I) in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation contains, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound of Formula (I) is present at a level of about 1 -80 wt %.
  • the compound of Formula (I) can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of psychoses, especially schizophrenia and bipolar disorder, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's disease, cognitive impairment and/or memory loss, e.g., nicotinic a-7 agonists, PDE4 inhibitors, other PDE10 inhibitors, calcium channel blockers, muscarinic ml and m2 modulators, adenosine receptor modulators, ampakines, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and galanthanamine).
  • each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range, and can be administered either simultaneously or sequentially.
  • compositions of the present invention also include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the above combinations include combinations of a compound of Formula (I) not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor,
  • compositions of the present invention also include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • Drugs suitable in combination with the compounds of Formula (I) include, but are not limited to, other suitable schizophrenia drugs such as Clozaril, Zyprexa, Risperidone, and Seroquel; bipolar disorder drugs, including, but not limited to, Lithium, Zyprexa, and Depakote; Parkinson's disease drugs, including, but not limited to, Levodopa, Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin; agents used in the treatment of Alzheimer's disease, including, but not limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and Cliquinol; agents used in the treatment of dementia, including, but not limited to, Thioridazine, Haloperidol, Risperidone, Cognex, Aricept, and Exelon; agents used in the treatment of epilepsy, including, but not limited to, Tri
  • Risperidone agents useful in the treatment of diabetes, including, but not limited to, PPAR ligands (e.g. agonists, antagonists, such as Rosiglitazone, Troglitazone and Pioglitazone), insulin secretagogues (e.g., sulfonylurea drugs, such as Glyburide, Glimepiride,
  • PPAR ligands e.g. agonists, antagonists, such as Rosiglitazone, Troglitazone and Pioglitazone
  • insulin secretagogues e.g., sulfonylurea drugs, such as Glyburide, Glimepiride,
  • cc-glucosidase inhibitors such as Acarbose, Miglitol, and Voglibose
  • insulin sensitizers such as the PPAR- ⁇ agonists, e.g., the glitazones; biguanides, PTP-1B inhibitors, DPP-IV inhibitors, and 1 lbeta- HSD inhibitors
  • hepatic glucose output lowering compounds such as glucagon antagonists and metaformin, e.g., Glucophage and Glucophage XR
  • insulin and insulin derivatives both long and short acting forms and formulations of insulin
  • anti-obesity drugs including, but not limited to, ⁇ -3 agonists, CB-1 agonists, neuropeptide Y5 inhibitors, Ciliary Neurotrophic Factor and derivatives (e.g., Axokine), appetite suppressants (e
  • the compound of Formula (I) may be administered in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, and anti- amyloid antibodies.
  • the compound of the present invention may be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, PDE10 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone
  • trimipramine trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, Zolpidem, and salts thereof, and combinations thereof.
  • the compound of Formula (I) may be administered in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and prarnipexole.
  • levodopa with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide
  • anticholinergics
  • the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • a pharmaceutically acceptable salt for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • Lisuride and pramipexol are commonly used in a non-salt form.
  • the compound of Formula (I) may be administered in combination with a compound from the phenothiazine, thioxanthene, heterocyclic
  • dibenzazepine butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • the compound of the present invention may be administered in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol,
  • the compound of Formula (I) may be administered in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRls), corticotropin releasing factor (CRF) antagonists, adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants, benzodiazopines, 5-HTA agonists or antagonists, especially 5-HTA partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • norepinephrine reuptake inhibitors including tertiary amine tricyclics and secondary amine tricyclics
  • Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide, venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazopam, chlorazepate, diazopam, halazepam, lorazepam, oxazopam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) may be administered orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles, for the treatment of PDE10- related diseases, such as acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed- vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary,
  • parenteral as used herein includes, subcutaneous, intravenous,
  • Treatment of diseases and disorders herein is intended to also include the prophylactic administration of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject (i.e., an animal, preferably a mammal, most preferably a human) believed to be in need of preventative treatment, such as, for example, pain, inflammation and the like.
  • a subject i.e., an animal, preferably a mammal, most preferably a human
  • preventative treatment such as, for example, pain, inflammation and the like.
  • the dosage regimen for treating PDElO-receptor-mediated diseases, cancer, and/or hyperglycemia with the compounds of Formula (I) and/or compositions of this invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. Dosage levels of the order from about 0.01 mg to 30 mg per kilogram of body weight per day, preferably from about 0.1 mg to 10 mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for all methods of use disclosed herein.
  • the pharmaceutically active compounds of Formula (I) can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
  • the pharmaceutical composition may be in the form of, for example, a capsule, a tablet, a suspension, or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient.
  • these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg, more preferably from about 5 to 150 mg.
  • a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.
  • the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water.
  • suitable carriers including saline, dextrose, or water.
  • the daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1 mg/kg.
  • Injectable preparations such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known are using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily.
  • the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.
  • liquid or semi-liquid preparations suitable for penetration through the skin e.g., liniments, lotions, ointments, creams, or pastes
  • drops suitable for administration to the eye, ear, or nose e.g., liniments, lotions, ointments, creams, or pastes
  • the compounds of Formula (I) are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • the compounds of Formula (I) may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • Other adjuvants and modes of administration are well known in the pharmaceutical art.
  • the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the pharmaceutical compositions may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions).
  • the pharmaceutical compositions may be subjected to conventional
  • compositions such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
  • Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of
  • optically active acids examples include tartaric, diacetyltartaric, dibenzoyltartaric,
  • diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
  • the optically active compounds of the invention can likewise be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • the compounds of Formula (I) may exist as isomers, that is compounds of the same molecular formula but in which the atoms, relative to one another, are arranged differently.
  • the alkylene substituents of the compounds of this invention are normally and preferably arranged and inserted into the molecules as indicated in the definitions for each of these groups, being read from left to right.
  • the substituent to be inserted may be the same as that noted above except that it is inserted into the molecule in the reverse orientation.
  • these isomeric forms of the compounds of Formula (I) are to be construed as encompassed within the scope of the present invention.
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • the organic salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulf
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as de
  • inorganic acids that may be employed to from pharmaceutically acceptable acid addition salts include hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.
  • Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
  • esters of a carboxylic acid or hydroxyl containing group including a metabolically labile ester or a prodrug form of a compound of this invention.
  • a metabolically labile ester is one which may produce, for example, an increase in blood levels and prolong the efficacy of the corresponding non-esterified form of the compound.
  • a prodrug form is one which is not in an active form of the molecule as administered but which becomes therapeutically active after some in vivo activity or biotransformation, such as metabolism, for example, enzymatic or hydro lytic cleavage.
  • esters for example, methyl, ethyl
  • cycloalkyl for example, cyclohexyl
  • aralkyl for example, benzyl, p- methoxybenzyl
  • alkylcarbonyloxyalkyl for example, pivaloyloxymethyl
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • Esters of a compound of this invention may include, for example, the methyl, ethyl, propyl, and butyl esters, as well as other suitable esters formed between an acidic moiety and a hydroxyl containing moiety.
  • Metabolically labile esters may include, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl, -methoxy ethyl, groups such as -((Ci-C4)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-l,3- dioxolen-4-ylmethyl groups, such as 5-methyl-2-oxo-l,3,dioxolen-4-ylmethyl, etc.; C1-C3 alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl, isopropy
  • the compounds of the invention may exist as crystalline solids which can be crystallized from common solvents such as ethanol, ⁇ , ⁇ -dimethyl-formamide, water, or the like.
  • crystalline forms of the compounds of the invention may exist as polymorphs, solvates and/or hydrates of the parent compounds or their pharmaceutically acceptable salts. All of such forms likewise are to be construed as falling within the scope of the invention.
  • HATU 0-(7-Azobenzotriazol- 1 -yl)- 1, 1,3,3 -tetramethyluronium hexafluorophosphate.
  • HBTU l-[bis(dimethylamino)methylene]-lH-benzotriazolium 3-oxide hexafluorophosphate
  • tert-Butyl (trans-3 -aminocyclobutyl)carbamate and tert-Butyl (cis-3- aminocyclobutyl)carbamate which were used as starting materials in the following synthesis of one or more intermediate compounds, were synthesized according to published literature procedures, specifically Radchenko, D. S., Pavlenko, S. O., et al., J. Org. Chem. 2010, 75, 5941-5952.
  • STEP 1 TERT-BOTY (rR ⁇ N5-3-((3-NITROPYRIDrN-2-YL)AMINO)CYCLOBUTYL) CARBAMATE
  • STEP 3 TERT- U YL (m4N5 , -3-((3-(CYCLOPROPANECARBOXAMIDO)PYRIDTN-2- YL)AMINO)CYCLOBUTYL)CARBAMATE
  • the crude acid chloride was further dried under high vacuum then dissolved in dry tetrahydrofuran (20 mL) and slowly added to an ice cooled solution of sodium borohydride (2.5 g, 66.1 mmol) in water (100 mL with about 80 mL of ice) over 40 minutes. The reaction was stirred for an additional 15 minutes. Ethyl acetate (400 mL) and additional water (100 mL) were added and the phases stirred. Sodium hydroxide (5 N, 40 mL) was added to make the aqueous layer basic. The mixed phases were stirred for 2 hours then the layers were separated. The organic layer was dried with magnesium sulfate before evaporating to dryness under reduced pressure.
  • l-(2-Chloropyridin-3-yl)cyclopropanecarbonitrile was synthesized analogous to l-(2-chloro-5-fluoropyridin-3-yl)cyclopropanecarbonitrile (Intermediate 15) using (2- chloropyridin-3-yl)acetonitrile as a reactant in place of 2-(2-chloro-5-fluoropyridin-3-yl) acetonitrile.
  • STEP 2 TERT-BOTY (rR/iNS-3-(3,3-DIMETHYL-2-OXO-2,3-DiHYDRO-lH- P YRROLO [2 , 3 -B] P YRIDIN- 1 - YL)CYCLOBUT YL)C ARB AMATE
  • step 2 To the product from step 2 was added ethyl acetate (10 mL) followed by 4 M hydrogen chloride in 1,4-dioxane (3649 ⁇ , 14.60 mmol). After stirring at room temperature for 3 hours, the precipitate was collected by filtration, washed with additional ethyl acetate, and dried to give l-(?ra «s-3-aminocyclobutyl)-3,3-dimethyl-lH-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (680 mg, 2.54 mmol, 87 % yield) as tan solid.
  • INTERMEDIATE 27 m4N5 , -Nl-(BENZO[D]THIAZOL-2-YL)-N 3 -(3-CHLOROPYRAZTN- 2 -YL)CYCLOBUT ANE- 1 , 3 -DIAMINE

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Abstract

La présente invention concerne des composés hétérobicycliques de formule (I) comprenant : (I) ou un sel pharmaceutiquement acceptable, un tautomère, ou un stéréoisomère de ceux-ci, tels que définis dans la description, et des compositions les contenant, et des procédés pour la préparation de tels composés. La présente invention concerne également des procédés de traitement d'affections ou de maladies pouvant être traitées par l'inhibition de la PDE10, telles que l'obésité, le diabète non insulino-dépendant, la schizophrénie, le trouble bipolaire, le trouble obsessionnel-compulsif, la maladie de Huntington et similaires.
PCT/US2013/028436 2012-02-29 2013-02-28 Composés hétérobicycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase WO2013130890A1 (fr)

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JP2014560058A JP2015508826A (ja) 2012-02-29 2013-02-28 複素二環式化合物、及びホスホジエステラーゼ阻害剤としてのそれらの使用
CA2865980A CA2865980A1 (fr) 2012-02-29 2013-02-28 Composes heterobicycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase
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MX2014010377A (es) 2014-10-23
EP2820014A1 (fr) 2015-01-07
CA2865980A1 (fr) 2013-09-06
TW201348231A (zh) 2013-12-01
AR090203A1 (es) 2014-10-29
UY34649A (es) 2013-09-30
AU2013225838A1 (en) 2014-09-11
US20130225552A1 (en) 2013-08-29
JP2015508826A (ja) 2015-03-23

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